The Cardiometabolic microRNA Laboratory studies how microRNAs alter the expression of key genes involved in the pathogenesis of atherosclerosis and other chronic inflammatory diseases, such as type II diabetes. The team also studies novel mechanisms of inflammation that promote plaque vulnerability. We employ animal models of human disease, in vitro assays of inflammation, cholesterol homeostasis and cellular activation, and analyze pathways of interest in human plasma and atherosclerotic plaque samples.
The laboratory is funded by the Canadian Institutes of Health Research (CIHR), the Heart and Stroke Foundation of Canada (HSFC) and the National Institutes of Health (NIH).
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Driven by the interplay between accumulation of excess cholesterol in the arterial wall and the immune system, atherosclerosis is a disease of maladaptive inflammation. The atherosclerotic plaque grows when the rate of macrophage accumulation (via recruitment and proliferation) exceeds that of removal (e.g., via cell death and egress). The removal of excess cholesterol is intricately linked to the inflammatory status of lesions, which in turn underlies the susceptibility to plaque rupture- the ultimate clinical complication of atherosclerosis. Our laboratory recently discovered the role of microRNAs as major regulators of macrophage function in atherosclerosis progression. We have identified the unique coupling of microRNAs to the metabolic and energy control of macrophages and cholesterol removal from lesions, and these discoveries open entirely new avenues to attenuate or reverse the atherosclerotic plaque and its resultant complications. The overall goals of my research program are to discover novel mechanisms that underlie plaque progression and vulnerability, and translate these into tools to ameliorate its clinical impact.
Accordingly, our research program focuses on three integrated research themes: (1) how microRNAs alter macrophage function via extracellular signalling mechanisms; (2) how energy metabolism and metabolic dysregulation within inflammatory cells contributes to atherosclerosis; and (3) how inflammation triggers plaque instability and how this can be used as a diagnostic tool for patients with atherosclerotic disease.
Theme #1: Elucidation and therapeutic targeting of extracellular microRNA mechanisms in macrophages
Research objectives: The power of miRNA-based post-transcriptional regulation is amplified by the fact that miRNAs can be secreted into the extracellular space to serve as second messengers of cellular communication to neighbouring and distant cells3. We find that a number of miRNAs are significantly enriched or down-regulated in foam cell exosomes and are predicted to regulate inflammatory pathways and macrophage polarization (M1/M2). We are testing how miRNA-loaded exosomes alter macrophage function in vitro and the propagation of inflammation in atherosclerosis in vivo. We will aim to develop therapeutic anti-sense miRNA and lipid nanoparticles (LNPs) that mimic exosomes for delivery of miRNAs for therapeutic use which are amenable to in vivo imaging if labelled with PET or SPECT tracers that we are currently developing.
Theme #2: The reversal of atherosclerotic vascular disease: beyond prevention
How can we reverse atherosclerosis?
In an era of unprecedented LDL lowering, at-risk patients have multiple options to achieve optimal circulating LDL levels. Despite this, in people for whom cholesterol levels are well-managed, there is significant risk of heart attack or adverse cardiovascular events, a phenomenon now termed the “residual inflammatory risk”. Recent clinical trials have demonstrated that blocking inflammatory pathways in these patients reduces heart attack and stroke, even when LDL levels are low. The inflammatory pathways that contribute to atherosclerosis continue to be elucidated, and involve both the innate and the adaptive immune systems. Yet, our understanding of how inflammation resolves within the plaque, or rather fails to, is less than complete. In order to regress atherosclerotic lesions, tissue repair and remodelling are needed and require the initiation of anti-inflammatory and pro-reparative pathways. The primary mechanism of plaque regression is through macrophage turnover, either by cell death and efficient removal by phagocytes, or by migration of mature macrophages out of the plaque. We will study these aspects of lesion dynamics but now with a focus on how to promote resolution of inflammation and plaque regression, with the following 3 main questions:
- How do pro-resolving signalling pathways become impaired in advanced atherosclerotic disease?
- Do non-coding RNAs act as regulators of cell survival and cell death signals in the plaque?
- What is the regulation of macrophage metabolism and inflammatory phenotype? during lesion regression?
- Raggi P, Genest J, Giles JT, Rayner KJ, Dwivedi G, Beanlands RS, Gupta M. Atherosclerosis. 2018 Sep;276:98-108. Role of inflammation in the pathogenesis of atherosclerosis and therapeutic interventions
- Nguyen MA, Karunakaran D, Geoffrion M, Cheng HS, Tandoc K, Perisic Matic L, Hedin U, Maegdefessel L, Fish JE, Rayner KJ. Arterioscler Thromb Vasc Biol. 2018 Jan;38(1):49-63. Extracellular Vesicles Secreted by Atherogenic Macrophages Transfer MicroRNA to Inhibit Cell Migration.
- Rayner KJ. Arterioscler Thromb Vasc Biol. 2017 Jul;37(7):e75-e81. doi: 10.1161/ATVBAHA.117.309229. Review. Cell Death in the Vessel Wall: The Good, the Bad, the Ugly.
- Karunakaran D, Geoffrion M, Wei L, Gan W, Richards L, Shangari P, DeKemp EM, Beanlands RA, Perisic L, Maegdefessel L, Hedin U, Sad S, Guo L, Kolodgie FD, Virmani R, Ruddy T, Rayner KJ. Sci Adv. 2016 Jul 22;2(7):e1600224. doi: 10.1126/sciadv.1600224. eCollection 2016 Jul. Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis.
- Karunakaran D, Thrush AB, Nguyen MA, Richards L, Geoffrion M, Singaravelu R, Ramphos E, Shangari P, Ouimet M, Pezacki JP, Moore KJ, Perisic L, Maegdefessel L, Hedin U, Harper ME, Rayner KJ. Circ Res. 2015 Jul 17;117(3):266-78. Macrophage Mitochondrial Energy Status Regulates Cholesterol Efflux and Is Enhanced by Anti-miR33 in Atherosclerosis.
- Rayner KJ. miR-155 in the Heart: The Right Time at the Right Place in the Right Cell. Circulation. 2015 Apr 7.
- Rayner KJ, Esau EC, Hussain FN, McDaniel AL, Marshall SM, van Gils JM, Ray TD, Sheedy FJ, Goedeke L, Liu X, Khatsenko OG, Kaimal V, Lees CJ, Fernandez-Hernando C, Fisher EA, Temel RE, Moore KJ. Inhibition of miR-33a and b in non-human primates raises plasma HDL cholesterol and reduces VLDL triglycerides. Nature. 2011; 478(7369):404-7.
- Rayner KJ, Sheedy FJ, Esau EC, Hussain FN, Temel RE, Parathath, van Gils JM, Rayner AJ, Chang AN, Suarez Y, Fernandez-Hernando C, Fisher EA, Moore KJ. Antagonism of miR-33 in Mice Promotes Reverse Cholesterol Transport and Regression of Atherosclerosis. Journal of Clinical Investigation. 2011; 21(7):2921-31.
- Rayner KJ*, Suarez Y*, Davalos A, Parathath S, Fitzgerald ML, Tamehiro N, Fisher EA, Moore KJ# and Fernandez-Hernando C#. miR-33 Contributes to the Regulation of Cholesterol Homeostasis. Science. 2010; 328(5985):1570-3. *,# Equal contribution.
Current Team Members
- Anne-Claire Duchez, PhD, Postdoctoral Fellow
- Adil Rasheed, PhD, Postdocoral Fellow
- My Anh Nguyen, MSc, PhD candidate
- Leah Susser, MSc candidate
- Mary-Lynn Cottee, MSc candidate
- Michele Geoffrion, Laboratory Manager